Mesothelin as a biomarker for clinical management of esophageal adenocarcinoma

描述(申请人提供)：一项评估间硫蛋白作为食管腺癌(EAC)患者临床治疗生物标记物的前瞻性临床试验食管腺癌(EAC)的发病率正以每年8%的速度上升。大多数EAC患者处于疾病晚期，总体5年存活率为10%。在出现潜在可治愈疾病的患者中，大多数人已经患有局部地区晚期疾病。尽管综合治疗是目前治疗局部晚期疾病的标准，可以提高存活率，但缺乏对肿瘤负担和治疗反应的准确临床评估，这是及时选择适当治疗的一个重大限制。尽管进行了放射检查和内窥镜检查，但每四名假定为早期疾病的患者中，就有一人在手术时被发现有更广泛的疾病(T3或N1)。这些患者本可以从多模式治疗中受益。在接受局部晚期疾病新辅助治疗的患者中，对治疗反应的评估仍然不准确。识别和验证反映肿瘤负担、治疗反应和复发的生物标记物将对EAC患者的临床管理和临床试验具有很高的价值。在这项研究方案中，基于我们有希望的回顾数据，我们的目标是研究血清和组织间硫蛋白作为生物标记物来改善EAC患者的临床治疗。间皮蛋白是一种细胞表面肿瘤分化抗原，其N-端被切割并分泌到血液中，测定为血清中的可溶性间皮蛋白相关肽(SMRP)。间皮瘤、胰腺癌和卵巢癌患者的SMRP水平升高。最近的研究表明，SMRP水平与间皮瘤患者的肿瘤负荷、治疗反应和预后相关。我们建议：特定目标1：前瞻性评估血清SMRP水平是否与(A)临床分期、(B)对新辅助治疗的反应和(C)手术切除EAC患者的疾病复发相关。具体目的2：前瞻性研究组织间皮间充质蛋白表达(A)放化疗前是否预示着不良的治疗反应，以及(B)术后是否预示着不良的生存。这项精心设计的前瞻性建议的新颖性和影响超出了生物标记物研究的范围，测试了间甲肾上腺素作为巴雷特向EAC转变的标记物的效用；它立即 翻译，使15,000名EAC患者受益。 公共卫生相关性：一种简单的预测工具，可以识别早期食管腺癌患者，治疗反应差和复发的风险较高；因此，最有可能选择治疗方式或积极监测的候选人将受益。在这项研究方案中，基于我们有希望的回顾数据，我们的目标是研究血清和组织中的间硫蛋白作为一个生物标志物来改善食管腺癌患者的临床治疗。

DESCRIPTION (provided by applicant): A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Esophageal Adenocarcinoma (EAC) Patients The incidence of esophageal adenocarcinoma (EAC) is rising at an annual rate of 8%. Most EAC patients present at an advanced stage disease with an overall 5-year survival rate of 10%. Of the patients who present with potentially curable disease, majority will already have local-regional advanced disease. Although combined modality treatment, the current standard of care for locally advanced disease, improves survival, lack of accurate clinical evaluation of tumor burden and treatment response is a significant limitation in selecting appropriate treatment in a timely fashion. In spite of the radiographic and endoscopic imaging, one in four patients with a presumed early-stage disease are found to have more extensive disease (T3 or N1) at the time of surgery. These patients would have benefited from multimodality therapy. In patients treated with neo- adjuvant therapy for local-regional advanced disease, assessment of therapy response remains inaccurate. Identification and validation of a biomarker that reflects tumor burden, therapy response, and recurrence will be highly valuable for the clinical management and clinical trials of EAC patients. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of EAC patients. Mesothelin is a cell surface tumor-differentiation antigen, the N-terminal of which is cleaved and secreted into blood, measured as serum soluble mesothelin-related peptide (SMRP). Increased SMRP levels are demonstrated in mesothelioma, pancreatic and ovarian cancer patients. Recent publications have demonstrated that the level of SMRP correlates with tumor load, therapy response, and prognosis in mesothelioma patients. We propose: Specific Aim 1: To prospectively evaluate whether serum SMRP levels correlate with (a) clinical staging, (b) response to neo-adjuvant therapy, and (c) disease recurrence in surgically resected EAC patients. Specific Aim 2: To prospectively investigate whether tissue mesothelin expression (a) pre chemo-radiation therapy is a predictor of poor therapy response, and (b) post-resection is a predictor of poor survival. The novelty and impact of this carefully designed prospective proposal extends beyond biomarker study in testing the utility of mesothelin as a marker of Barrett's transformation to EAC; it is immediately translational to benefit 15,000 patients with EAC. PUBLIC HEALTH RELEVANCE: A simple predictive instrument to identify early-stage esophageal adenocarcinoma patients at higher risk for poor therapy response and recurrence; therefore the most likely candidates for selection of therapeutic modality or aggressive surveillance will benefit. In this research proposal, based on our promising retrospective data, we aim to investigate serum and tissue mesothelin as a biomarker to improve the clinical management of esophageal adenocarcinoma patients.